The objectives of this project are to extend studies on proinsulin, insulin, and related polypeptides in the following specific areas: Extension of studies on the structures and chemical properties of proinsulin from various vertebrates; the primary structures of proinsulin and insulin in diabetic humans as well as in primitive vertebrate and non-vertebrate species; characterization and isolation of the cellular proteolytic enzymes responsible for the conversion of proinsulin to insulin; the metabolism of proinsulin and C-peptide in man and other species, including distribution, degradation and excretion; improvement of specific immunological methods of measurement of human proinsulin and C-peptide in biological fluids; biosynthesis of other polypeptide hormones such as glucagon; intracellular localization of insulin and related peptides in diabetic and normal rat liver; the biochemical consequences of insulin binding in the liver that lead to increased nuclear RNA synthesis.